The intestine serves a barrier function that is a critical component of the innate immune system. Only a single layer of epithelial cells separates the luminal contents from effector immune cells in the lamina propria and the internal milieu of the body. Breaching this single layer of epithelium can lead to pathologic exposure of the highly immunoreactive subepithelium to the vast number of microbes and antigens in the lumen. Breakdown of the barrier is implicated in the pathogenesis of acute illnesses such as multiple organ system failure and bacterial translocation leading to sepsis.
Defective functioning of the intestine as a barrier against infection can occur in individuals of all ages. However, the elderly and the very young are particularly suspectible. For example, because of feeding intolerance and the fear of necrotizing enterocolitis (NEC), many premature infants undergo a period of “luminal starvation” during which time these infants receive very little, if any, food via the gastrointestinal tract and are nourished primarily by the intravenous route with total parenteral nutrition (TPN). A lack of enteral nutrients with TPN contributes to mucosal breakdown, bacterial translocation and an increased propensity to systemic inflammation (Huang Y, Li N, Liboni K, Neu J “Glutamine decreases endotoxin-induced IL-8 production in Caco-2 cells via non-NF kappa-B pathways” Cytokine. 2003 May; 22(3-4): 77-88).
The preterm, especially the very low birthweight preterm infant, is frequently also highly stressed because of respiratory insufficiency, thermoregulation, and other challenges. The trend in the past decade has been to provide greater amino acids by the parenteral route (Liboni K, Li N, Neu J. “Mechanism of Glutamine-mediated amelioration of lipopolysaccharide-induced IL-8 production in Caco-2 cells” Cytokine. 2004 Apr. 21; 26(2):57-65; Beierle E A, Chen M K, Hartwich J E, Iyengar M, Dai W, Li N, Demarco V, Neu J. “Artificial rearing of mouse pups: development of a mouse pup in a cup model” Pediatr Res. 2004 August; 56(2): 250-5.) in the acute phase of illness in the first weeks after birth, then to transition to human milk or formula by the enteral route. This is inadequate because any enteral nutrition provided in the first weeks of life is usually in the form of “minimal enteral nutrition” (roughly defined as an amount of nutrition that does not meet the nutritional requirements for growth but confers some benefit, and is usually less than 20% of the total nutritional requirements) (Liboni, K, Li N, Scumpia P O, Neu J. “Glutamine Modulates LPS-Induced IL-8 Production. Through IκB/NF-κB in Human Fetal and Adult Intestinal Epithelium” Journal of Nutrition 2005 February; 135(2): 245-51; Liu Z, Li N, Neu J. “Tight junctions, leaky intestines and pediatric diseases” Acta Paediatrica 2005; 94:386-393; Zhang L, Li N, Caicedo R, Neu J. “Lactobacillus Rhamnosus G G Dead or Alive Decreases Tumor Necrosis Factor-α Induced IL-8 Production in Caco-2 cells” Journal of Nutrition 2005 July; 135(7):1752-6.)
Despite often being termed “trophic nutrition” minimal enteral nutrition along with parenteral nutrition (PN) does not provide a significant trophic effect on the intestine nor does it enhance barrier function (Zhang L, Li N, desRobert C, Fang M, Liboni K, McMahon R, Caicedo R, Neu J. “Lactobacillus Rhamnosus GG Decreases Lipopolysaccharide-Induced Systemic Inflammation in A Gastrostomy-Fed Infant Rat Model” Journal of Pediatric Gastroenterology and Nutrition May, 2006 42:545-552; Neu, J. “The ‘myth’ of asphyxia and hypoxia-ischemia as primary causes of necrotizing enterocolitis” Biol Neonate. 2005; 87(2):97-8; Neu J, Chen M, Beierle E “Intestinal innate immunity: how does it relate to the pathogenesis of necrotizing enterocolitis?” Semin Pediatr Surg. 2005 August; 14(3):137-44). Moreover, it is clear that the use of TPN is significantly associated with hospital acquired sepsis (Caicedo R A, Schanler R J, Li N, Neu J. “The developing intestinal ecosystem: implications for the neonate” Pediatr Res. 2005 October; 58(4):625-8), which is partially caused by translocation of intestinal bacteria (Li N, Lassman B J, Liu Z., Liboni, K., Neu, J. “The Effects of Protein Deprivation on Growth and Small Intestine Morphology Are Not Ameliorated By Glutamine or Glutamate in Gastrostomy-Fed Rat Pups” J. Pediatric Gastroenterology and Nutrition 2004 July; 39(1):28-33; Neu J, Zhang L. “Feeding intolerance in very-low-birthweight infants: what is it and what can we do about it?” Acta Paediatr Suppl. 2005 October; 94(449):93-9).
Although the recent trends toward early increases in intravenous protein intake may provide benefits in terms of protein synthesis, decreased catabolism, and perhaps even somatic growth (Beierle E A, Chen M K, Hartwich J E, Iyengar M, Dai W, Li N, Demarco V, Neu J. “Artificial rearing of mouse pups: development of a mouse pup in a cup model” Pediatr Res. 2004 August; 56(2): 250-5; Neu J. “Gastrointestinal maturation and feeding” Semen Perinatal. 2006 April; 30(2):77-80), this practice does not promote or maintain gastrointestinal barrier function or optimal growth of the GI tract, which is a prerequisite for modulation of several disease processes where intestine mediated breakdown and systemic inflammation play a role. These include NEC, hepatic inflammation, chronic lung disease and progression of periventricular leukomalacia.
There is thus a great need for enteral adjuncts shortly after birth that will decrease the need for parenteral nutrition. A safe and effective “starter formula” that enhances intestinal growth and improves barrier function is needed for sick low birthweight infants. Such a preparation would be used as an adjunct to early aggressive parenteral nutrition and other enteral nutrients such as human milk.